Two poly (ADP-ribose) polymerase (PARP) inhibitors (olaparib and rucaparib) are US Food and Drug Administration-approved for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring BRCA1/2 mutations, but the relative efficacy of PARP inhibition in BRCA1- versus BRCA2-altered mCRPC is understudied.
We conducted a multicenter retrospective analysis involving 12 sites. We collected genomic and clinical data from 123 patients with BRCA1/2-altered mCRPC who were treated with PARP inhibitors. The primary efficacy end point was the prostate-specific antigen (PSA) response (≥ 50% PSA decline) rate. Secondary end points were PSA progression-free survival (PSA-PFS), clinical or radiographic PFS, and overall survival. We compared clinical outcomes, and other genomic characteristics, among BRCA1- versus BRCA2-altered mCRPC.
A total of 123 patients (13 BRCA1 and 110 BRCA2) were included. PARP inhibitors used were olaparib (n = 116), rucaparib (n = 3), talazoparib (n = 2), and veliparib (n = 2). At diagnosis, 72% of patients had Gleason 8-10 disease. BRCA1 patients were more likely to have metastatic disease at presentation (69% v 37%; P = .04). Age, baseline PSA, metastatic distribution, and types of previous systemic therapies were similar between groups. There were equal proportions of germline mutations (51% v 46%; P = .78) in both groups. BRCA1 patients had more monoallelic (56% v 41%; P = .49) and concurrent TP53 (55% v 36%; P = .32) mutations. PSA50 responses in BRCA1- versus BRCA2-altered patients were 23% versus 63%, respectively (P = .01). BRCA2 patients achieved longer PSA-PFS (HR, 1.94; 95% CI, 0.92 to 4.09; P = .08), PFS (HR, 2.08; 95% CI, 0.99 to 4.40; P = .05), and overall survival (HR, 3.01; 95% CI, 1.32 to 6.83; P = .008). Biallelic (compared with monoallelic) mutations, truncating (compared with missense) mutations, and absence of a concurrent TP53 mutation were associated with PARP inhibitor sensitivity.
PARP inhibitor efficacy is diminished in BRCA1- versus BRCA2-altered mCRPC. This is not due to an imbalance in germline mutations but might be related to more monoallelic mutations and/or concurrent TP53 alterations in the BRCA1 group.
JCO precision oncology. 2021 Jul 22*** epublish ***
Fadi Taza, Albert E Holler, Wei Fu, Hao Wang, Nabil Adra, Costantine Albany, Ryan Ashkar, Heather H Cheng, Alexandra O Sokolova, Neeraj Agarwal, Adam Kessel, Alan Bryce, Nellie Nafissi, Pedro Barata, A Oliver Sartor, Diogo Bastos, Oren Smaletz, Jacob E Berchuck, Mary-Ellen Taplin, Rahul Aggarwal, Cora N Sternberg, Panagiotis J Vlachostergios, Ajjai S Alva, Christopher Su, Catherine H Marshall, Emmanuel S Antonarakis
Johns Hopkins University School of Medicine, Baltimore, MD., Indiana University School of Medicine, Indianapolis, IN., University of Washington and Fred Hutch Cancer Research Center Seattle, Washington, DC., Huntsman Cancer Institute, University of Utah, Salt Lake City, UT., Mayo Clinic, Scottsdale, AZ., Tulane University School of Medicine, New Orleans, LA., Oncology Center, Hospital Sírio-Libanês, São Paulo, Brazil., Hospital Israelita Albert Einstein, São Paulo, Brazil., Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., University of California San Francisco, San Francisco, CA., Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY., University of Michigan, Ann Arbor, MI.